The long-term objective of this project is to develop a commercial product for the topical treatment of acne and skin diseases. The specific aim of the proposal is to invent a prodrug that can be used effectively and safely for the topial treatment of acne. Since isotretinoin (13-cis-retinoic acid, Accutane-Roche) administered orally gives birth defects and applied topicaly is irritating, we have designed prodrugs of isotretinoin. These prodrugs are intended (1) to be applied topically, (2) to make isotretinoin bioavailable at the target site by hydrolysis of the prodrug in the skin, and (3) to be effective and safe in the treatment of acne. Three prodrugs have already been synthesized and tested in the Topical Rhino Mouse Assay and the Oral Hamster Sebaceous Gland Assay. One of our compounds, MDI 3831101, is as effective as isotretinoin in the same assays. Since this is a new compound, a patent application has been filed. We propose to synthesize additional samples of MDI 3831101 and additional prodrugs of isotretinoin in order to optimize our lead compound.